Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice

Monica Fedele, Vincenzo Fidanza, Sabrina Battista, Francesca Pentimalli, Andres J P Klein-Szanto, Rosa Visone, Ivana De Martino, Antonio Curcio, Carmine Morisco, Luigi Del Vecchio, Gustavo Baldassarre, Claudio Arra, Giuseppe Viglietto, Ciro Indolfi, Carlo M. Croce, Alfredo Fusco

Research output: Contribution to journalArticle

Abstract

The HMGA1 protein is a major factor in chromatin architecture and gene control. It plays a critical role in neoplastic transformation. In fact, blockage of HMGA1 synthesis prevents rat thyroid cell transformation by marine transforming retroviruses, and an adenovirus carrying the HMGA1 gene in the antisense orientation induces apoptotic cell death in anaplastic human thyroid carcinoma cell lines, but not in normal thyroid cells. Moreover, both in vitro and in vivo studies have established the oncogenic role of the HMGA1 gene. In this study, to define HMGA1 function in vivo, we examined the consequences of disrupting the Hmgal gene in mice. Both heterozygous and homozygous mice for the Hmga1-null allele show cardiac hypertrophy due to the direct role of HMGA1 on cardiomyocytic cell growth regulation. These mice also developed hematologic malignancies, including B cell lymphoma and myeloid granuloerythroblastic leukemia. The B cell expansion and the increased expression of the RAG1/2 endonuclease, observed in HMGA1-knockout spleen tissues, might be responsible for the high rate of abnormal IgH rearrangements observed in these neoplasias. Therefore, the data reported here indicate the critical role of HMGA1 in heart development and growth, and reveal an unsuspected antioncogenic potential for this gene in hematologic malignancies.

Original languageEnglish
Pages (from-to)2536-2543
Number of pages8
JournalCancer Research
Volume66
Issue number5
DOIs
Publication statusPublished - Mar 1 2006

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Fedele, M., Fidanza, V., Battista, S., Pentimalli, F., Klein-Szanto, A. J. P., Visone, R., De Martino, I., Curcio, A., Morisco, C., Del Vecchio, L., Baldassarre, G., Arra, C., Viglietto, G., Indolfi, C., Croce, C. M., & Fusco, A. (2006). Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice. Cancer Research, 66(5), 2536-2543. https://doi.org/10.1158/0008-5472.CAN-05-1889